Lysine-40 succinylation of TAGLN2 induces glioma angiogenesis and tumor growth through regulating TMSB4X.

Protein lysine succinylation (K) represents an important regulatory mechanism of tumor development. In this work, the difference of protein K between HCMEC/D3 co-cultured with U87 (glioma endothelia cells, GEC) and without U87 (normal endothelia cells, NEC) was investigated using TMT labeling and affinity enrichment followed by high-resolution LC-MS/MS analysis. Interestingly, TAGLN2 was highly succinylated at K40 in GEC (15.36 folds vs. NEC). Compared to the Vector group, TAGLN2 and a succinylation-mimetic TAGLN2 greatly promoted the angiogenesis of glioma in vitro and in vivo. Furthermore, the adhesion and metastasis of U87 co-cultured with GEC in the TAGLN2 or TAGLN2 group were also significantly promoted. This was consistent with the increased expression of VE-cadherin and actin cytoskeleton remodeling induced by TAGLN2 K40succ in GEC. In addition, high K40succ of TAGLN2 was associated with poor prognosis in patients with glioma. Overexpression of TAGLN2 also markedly promoted the proliferation and migration of glioma cells, further analysis of in vivo xenograft tumors showed that there was a significant decrease in tumor size and angiogenesis in the TAGLN2 group. Notably, the co-localization of TMSB4X and TAGLN2 mainly in the nucleus and cytoplasm of glioma cells was detected by immunofluorescence staining. We identified TMSB4X as a potential target of TAGLN2, which was proved to interact with TAGLN2 rather than TAGLN2. And the inhibition of TMSB4X could markedly attenuate the proliferation and migration of glioma cells induced by TAGLN2 K40succ. The results revealed K40 of TAGLN2 could be a novelty diagnosis and therapeutic target for gliomas.